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Clinical trials are essential for advancing oncology treatment strategies and have contributed significantly to the decline in cancer mortality rates over the past decades. Traditional explanatory trials, focused on establishing intervention efficacy in ideal settings, often lack generalizability and may not reflect real-world patient care scenarios. Furthermore, increasing complexity in cancer clinical trial design has led to challenges such as protocol deviations, slow enrollment leading to lengthened durations of trial, and escalating costs. By contrast, pragmatic trials aim to assess intervention effectiveness in more representative patient populations under routine clinical conditions. Here, we review the principles, methodologies, challenges, and advantages of incorporating pragmatic features (PFs) into cancer clinical trials. We illustrate the application of pragmatic trial designs in oncology and discuss the QUASAR collaborative, TAPUR study, and the ongoing PRAGMATICA-LUNG trial. Although not all oncology trials may be amenable to adopting fully pragmatic designs, integration of PFs when feasible will enhance trial generalizability and real-world applicability. Project Pragmatica and similar initiatives advocate for the integration of real-world practice with clinical trials, fostering a nuanced approach to oncology research that balances efficacy and effectiveness assessments, ultimately with a goal of improving patient outcomes.

Therapeutic targeting of RAS-mutated cancers is difficult, whereas prevention or interception (treatment before or in the presence of preinvasive lesions) preclinically has proven easier. In the A/J mouse lung model, where different carcinogens induce tumors with different KRAS mutations, glucocorticoids and retinoid X receptor (RXR) agonists are effective agents in prevention and interception studies, irrespective of specific KRAS mutations. In rat azoxymethane-induced colon tumors (45% KRAS mutations), cyclooxygenase 1/2 inhibitors and difluoromethylornithine are effective in preventing or intercepting KRAS-mutated or wild-type tumors. In two KRAS-mutant pancreatic models multiple COX 1/2 inhibitors are effective. Furthermore, combining a COX and an EGFR inhibitor prevented the development of virtually all pancreatic tumors in transgenic mice. In the N-nitroso-N-methylurea-induced estrogen receptor-positive rat breast model (50% HRAS mutations) various selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, and RXR agonists are profoundly effective in prevention and interception of tumors with wild-type or mutant HRAS, while the farnesyltransferase inhibitor tipifarnib preferentially inhibits HRAS-mutant breast tumors. Thus, many agents not known to specifically inhibit the RAS pathway, are effective in an organ specific manner in preventing or intercepting RAS-mutated tumors. Finally, we discuss an alternative prevention and interception approach, employing vaccines to target KRAS., (©2023 American Association for Cancer Research.)

Purpose: Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC., Patients and Methods: S1507 is a single-arm phase II study assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients, with at least 25 with G12C mutation. The design was two-stage design to rule out a 17% RR, within the overall population at the one-sided 3% level and within the G12C subset at the 5% level., Results: Between July 18, 2016, and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% [95% confidence interval (CI), 22-48] overall and 28% (95% CI, 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, and neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR, 2.85; 95% CI, 1.16-7.01), and RR (0% vs. 56%, P = 0.004) were worse in patients with TP53 mutated versus wild-type cancers., Conclusions: RRs were significantly improved in the overall population. Contrary to preclinical studies, the combination showed no improvement in efficacy in G12C patients. Comutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation. See related commentary by Cantor and Aggarwal, p. 3563., (©2023 American Association for Cancer Research.)

Purpose: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access., Methods: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons., Results: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001)., Conclusion: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

There are major hurdles to the use of tyrosine kinase inhibitors (TKIs) and any other agents with significant toxicities (which means practically the preponderance of potential effective agents) in the context of prevention/anti-progression (interception) studies. We will discuss epidermal growth factor receptor (EGFR) inhibitors as examples, both in a primary prevention setting, where agent(s) are administered to individuals with no cancer but who might be considered at higher risk due to a variety of factors, and in anti-progression/interception studies, where agent(s) are administered to persons with known preinvasive lesions (e.g., colon adenomas, lung nodules, ductal carcinoma in situ (DCIS), or pancreatic intraepithelial neoplasia (PanIN) lesions in the pancreas) in an attempt to reverse or inhibit progression of these lesions. Multiple potential hurdles will be examined, including: a) toxicity of agents, b) the likely range of subtypes of cancers affected by a given treatment (e.g., EGFR inhibitors against EGFR mutant lung adenocarcinomas), c) the availability of practical endpoints besides the blocking of cancer formation or pharmacokinetics related to the agents administered in a primary prevention study, and d) the interpretation of the regression or blockage of new preinvasive lesions in the anti-progression study. Such an anti-progression approach may help address some of the factors commented on regarding primary prevention (toxicity, potential target organ cancer subtypes) but still leaves major questions regarding interpretation of modulation of preinvasive endpoints when it may not be clear how frequently they progress to clinical cancer. Additionally, we address whether certain recent preclinical findings might be able to reduce the toxicities associated with these agents and perhaps even increase their potential efficacy. Antibodies and TKIs other than the EGFR inhibitors are not discussed because few if any had been tested as monotherapies in humans, making their efficacy harder to predict, and because a number have relatively rare but quite striking toxicities. Furthermore, most of the practical hurdles raised regarding the EGFR inhibitors are relevant to the other TKIs. Finally, we briefly discuss whether early detection employing blood or serum samples may allow identification of high-risk groups more amenable to agents with greater toxicity., Competing Interests: KHD has received research funding to the institution from Roche/Genentech, Eli Lilly, Novartis, Amgen, Merck, Molecular Templates, Io Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dragnev, Dragnev and Lubet.)

The neoadjuvant use of immune checkpoint inhibitors (ICI) in resectable non-small cell lung cancer (NSCLC) is being increasingly adopted, but questions about the most appropriate applications remain. Although patients with resectable NSCLC are often treated with surgery and adjuvant chemotherapy or targeted therapies +/- radiotherapy, they still have a high risk of recurrence and death. In recent years, immune checkpoint inhibitors (ICI) (anti-PD-1/PD-L1 and anti-CTLA-4) have provided a new and effective therapeutic strategy for the treatment of advanced NSCLC. Therefore, it is possible that ICIs for early-stage NSCLC may follow the pattern established in metastatic disease. Currently, there are several ongoing trials to determine the efficacy in the neoadjuvant setting for patients with local or regional disease. To date, only nivolumab in combination with chemotherapy has been approved by the U.S. FDA in the preoperative setting, but data continue to evolve rapidly, and treatment guidelines need to be determined. In this article, we review the current preclinical and clinical evidence on neoadjuvant ICIs alone and combination in the treatment of early-stage NSCLC.

Background: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy., Methods: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1., Results: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GE high ) on the 5-gene panel was 29% (14/48), compared with low gene expression (GE low ) 3% (1/38, χ 2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GE high and GE low in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS., Conclusion: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab., Competing Interests: Competing interests: LCB declares the following relationships: Consulting with Seattle Genetics. JZ declares the following relationships: Consulting with Tempus. KD declares the following relationship: Consulting with Tyra BioSciences. EK declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. CK declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. YHL is/was an employee at OmniSeq. SP is/was an employee at OmniSeq. MKL declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. JT declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. KHD declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. LJT declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. FD declares that he has received research grants (to the institution) from AstraZeneca, Bristol Myers Squibb, Merck, Genentech/Roche, Taiho, Exelixis, Trishula, Leap Therapeutics, has received a speaker honorarium from Amgen, Eisai, Ipsen, Exelixis, Sirtex, Deciphera, Ipsen, Natera, and has received a consultancy honorarium from Natera, QED, Eisai, Exelixis, Genentech/Roche. RTG declares the following relationships: Bayer Pharma AG—consultant & speakers bureau, Invivo—consultant, Bard—consultant, DxTx Medical—consultant, Quibim—consultant, Bracco Diagnostics—consultant. SM declares the following relationships: AstraZeneca—consultant; Takeda Pharmaceuticals—speaker, honorarium. DJG declares the following relationships: Acerta Pharmaceuticals—research; American Association for Cancer Research—senior editor; Astellas—consultant, research, advisory board; AstraZeneca—consultant, advisory board; Axess Oncology—independent contractor; Bayer H/C Pharmaceuticals—research, consultant, speaker, honorarium, travel accommodations; SC, BMS—consultant, research, steering committee; Calithera—research; Capio Biosciences—scientific advisory board; EMD Serono—honorarium; Exelixis—research, consultant, speaker, honorarium, travel accommodations; Flatiron—consultant; Ipsen—honorarium; Janssen Pharmaceuticals—research, consultant, Independent Data Monitoring Committee; Leidos Biomedical Research—consultant; Merck Sharp & Dohme—consultant; Michael J Hennessey Associates—honorarium, consultant; Millennium Medical Publishing, Clinical Advances in Hematology & Oncology—co-editor-in-chief; Modra Pharmaceuticals B.V.—advisory board; Myovant Sciences—consultant; Nektar Therapeutics—steering committee; Novartis—research; Physician Education Resource LLC—consultant; Pfizer—research, consultant, steering committee, honorarium; Sanofi—research, consultant, speaker, honorarium, travel accommodations; UroGPO—honorarium; UroToday—honorarium, travel accommodations; Vizuri Health Sciences, LLC—consultant; NCI—steering committee. YHL is/was an employee at OmniSeq. STG is/was an employee at OmniSeq. MKN is/was an employee at OmniSeq. SG declares the following relationships: Aveo—advisory board, personal, advisor/consultant; Bayer—advisory board, personal, advisor/consultant; BMS—advisory board, personal, advisor/consultant; Corvus—advisory board, personal, advisor/consultant; Eisai—advisory board, personal, advisor/consultant; EMD Serono—advisory board, personal, advisor/consultant; Exelixis—advisory board, personal, advisor/consultant; Merck—advisory board, personal, advisor/consultant; Pfizer—advisory board, personal, advisor/consultant; QED Therapeutics—advisory board, personal, advisor/consultant; Sanofi/Genzyme—advisory board, personal, advisor/consultant; Seattle Genetics—advisory board, personal, advisor/consultant; Agensys—local PI, institutional, no financial interest; Aravive—local PI, institutional, no financial interest; Aveo—local PI, institutional, no financial interest; Bayer—local PI, institutional, no financial interest; BMS—local PI, institutional, no financial interest; Calithera—local PI, institutional, no financial interest; Corvus—local PI, institutional, no financial interest; Eisai—local PI, institutional, no financial interest; Exelixis—local PI, institutional, no financial interest; Gilead—local PI, institutional, no financial interest; Merck—local PI, institutional, no financial interest; Novartis—local PI, institutional, no financial interest; Pfizer—local PI, institutional, no financial interest; Seattle Genetics—local PI, institutional, no financial interest; Surface Oncology—local PI, institutional, no financial interest. MZ declares the following relationships: Consulting or advisory roles for: Exelixis, Pfizer, Aveo, EMD Serono, Janssen, Blue Earth; Institutional research funding from Bristol Myers Squibb, Exelixis. CM is/was an employee at OmniSeq. MCO declares the following relationships: Consulting or advisory roles for Eisai, Exelixis, Pfizer, Aveo, Merck, and Bristol Myers Squibb; speakers bureaus for Bristol Myers Squibb and Exelixis; institutional research funding from Bristol Myers Squibb, Pfizer, Merck, AstraZeneca, Astellas; reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, and Exelixis. TZ declares the following relationships: Research funding (to Duke University) from Pfizer, Janssen, Acerta, AbbVie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas, and Genentech; Speaking with Genomic Health and Sanofi Aventis; Consulting/Advisory board with AstraZeneca, Bayer, Pfizer, Janssen, Merck, Amgen, MJH Associates, BMS, Dendreon, Calithera, QED therapeutics, Aveo Therapeutics, Eli Lilly, SeaGen, Sanofi-Aventis, Pharmacyclics, Aptitude Health, PeerView, Clinical Care Options. Stock ownership/employment (spouse) from Capio Biosciences, Archimmune Therapeutics and Nanorobotics., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Resistance to immune checkpoint inhibition (ICI) in advanced non-small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types., Methods: In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity., Results: Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC., Conclusion: This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

Background: Despite progress in developing learning health systems (LHS) and associated metrics of success, a gap remains in identifying measures to guide the implementation and assessment of the impact of an oncology LHS. Our aim was to identify a balanced set of measures to guide a person-centered oncology LHS., Methods: A modified Delphi process and clinical value compass framework were used to prioritize measures for tracking LHS performance. A multidisciplinary group of 77 stakeholders, including people with cancer and family members, participated in 3 rounds of online voting followed by 50-minute discussions. Participants rated metrics on perceived importance to the LHS and discussed priorities., Results: Voting was completed by 94% of participants and prioritized 22 measures within 8 domains. Patient and caregiver factors included clinical health (Eastern Cooperative Oncology Group Performance Status, survival by cancer type and stage), functional health and quality of life (Patient Reported Outcomes Measurement Information System [PROMIS] Global-10, Distress Thermometer, Modified Caregiver Strain Index), experience of care (advance care planning, collaboRATE, PROMIS Self-Efficacy Scale, access to care, experience of care, end-of-life quality measures), and cost and resource use (avoidance and delay in accessing care and medications, financial hardship, total cost of care). Contextual factors included team well-being (Well-being Index; voluntary staff turnover); learning culture (Improvement Readiness, compliance with Commission on Cancer quality of care measures); scholarly engagement and productivity (institutional commitment and support for research, academic productivity index); and diversity, equity, inclusion, and belonging (screening and follow-up for social determinants of health, inclusivity of staff and patients)., Conclusions: The person-centered LHS value compass provides a balanced set of measures that oncology practices can use to monitor and evaluate improvement across multiple domains., (© The Author(s) 2022. Published by Oxford University Press.)

Background: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage small-cell lung cancer (ED-SCLC)., Patients and Methods: This was a parallel-cohort phase II study of 105 mg/m 2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m 2 days 1-3, 14-day cycle)., Results: In Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ≥3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified., Conclusion: Prexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chemotherapy-induced myelosuppression (CIM) and its sequalae cause significant side effects and harm to quality of life. Trilaciclib is an intravenous CDK4/6 inhibitor that is administered prior to chemotherapy to protect hematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection)., Patients and Methods: Data from three randomized, double-blind, placebo-controlled studies (NCT02499770, NCT03041311, and NCT02514447) were pooled to evaluate the effects of trilaciclib administered prior to standard-of-care chemotherapy (first-line etoposide plus carboplatin [E/P], first-line E/P plus atezolizumab, and second-/third-line topotecan) in patients with extensive-stage small cell lung cancer (ES-SCLC). The primary endpoints were duration of severe neutropenia (absolute neutrophil count < 0.5 × 10 9 cells/L) in cycle 1 and occurrence of severe neutropenia. Additional prespecified endpoints further assessed the effect of trilaciclib on myeloprotection, health-related quality of life (HRQoL), antitumor efficacy, and safety., Results: Of 242 randomized patients, 123 received trilaciclib and 119 received placebo. Compared with placebo, administration of trilaciclib prior to chemotherapy resulted in significant decreases in most measures of multilineage CIM. The reduction in hematologic toxicity translated into the reduced need for supportive care interventions and hospitalizations due to CIM or sepsis and improvements in HRQoL domains related to the protected cell lineages, including fatigue, physical wellbeing, and functional wellbeing. Antitumor efficacy was similar for patients receiving trilaciclib or placebo., Conclusion: Administering trilaciclib prior to chemotherapy resulted in clinically meaningful reductions in CIM and its consequences and improved patient HRQoL, with no impact on the antitumor efficacy of three individual chemotherapy regimens used in the first- or second-/third-line treatment of ES-SCLC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy., Methods: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a "pick a winner" design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years., Results: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%-54.1 %) and 40.4 % (95 % CI: 26.4%-54.5 %), respectively ( p  = 0.93). The progression-free survival in arms A and B was as follows: hazard ratio of B versus A equals to 1.06, 95 % CI: 0.68-1.66, p value equals to 0.84, and median progression-free survival of 5.8 months and 4 months, respectively. The overall survival was as follows: hazard ratio of B versus A equals to 1.04, 95 % CI: 0.63-1.74, p value equals to 0.85, and median overall survival of 15.5 months and 14 months, respectively., Conclusions: Additional evaluation of either sequence in a phase 3 trial is not warranted., (© 2021 The Authors.)

Background: There are limited data and conflicting guideline recommendations regarding the role of neuroimaging in the pretreatment evaluation of non-small cell lung cancer (NSCLC)., Methods: We performed a retrospective, pragmatic cohort study of patients with NSCLC diagnosed between January 1 and December 31, 2015. Eligible patients were identified from an institutional tumor registry. We collected all records of pretreatment neuroimaging within 12 weeks of diagnosis, including CT head (CT) and MRI brain (MRI). We abstracted the indication for neuroimaging, presence of central neurologic symptoms and cancer stage (with and without neuroimaging findings) from the tumor registry and the electronic health record., Results: We identified 216 evaluable patients with newly diagnosed NSCLC. 157 of 216 patients (72.7%) underwent neuroimaging as part of initial staging, and 41 (26%) were found to have brain metastases. Of 43 patients with central neurologic symptoms at the time of neuroimaging, 28 (67%) had brain metastasis. In patients without central neurologic symptoms, brain metastases were discovered in 0 of 33 patients with clinical stage I or II, 4 of 36 (11%) with clinical stage III and 9 of 45 (20%) with clinical stage IV disease., Conclusions: In patients with early stage NSCLC (i.e. clinical stage I and II) without central neurologic symptoms, brain metastases are unlikely. The continued use of neuroimaging in the pretreatment evaluation of clinical stage I patients without central neurologic symptoms is not needed., (© 2020 The Authors. Published by Elsevier Ltd.)

Matching of actionable tumor mutations with targeted therapy increases response rates and prolongs survival in lung cancer patients. Drug development and trials targeting genetic alterations are expanding rapidly. We describe the role of a Molecular Tumor Board (MTB) in the design of molecularly informed treatment strategies in our lung cancer patient population. Tumor DNA was sequenced using a 50-gene targeted next-generation sequencing panel. Cases were evaluated by a multidisciplinary MTB who suggested a course of treatment based on each patient's molecular findings. During a three-year period, 21 lung cancer patients were presented at the MTB. All patients lacked common activating EGFR mutations and ALK rearrangements. One patient had Stage IIIb disease; all others were Stage IV; 18 patients had received ≥1 prior line of therapy (range 0-5). Suggestions for treatment with a targeted therapy were made for 19/21 (90.5%) patients, and four patients (21%) underwent treatment with a targeted agent, two as part of a clinical trial. Identified barriers to treatment with targeted therapy included: ineligibility for clinical trials (n ​= ​2), lack of interest in study/distance to travel (n ​= ​2), lack of disease progression (n ​= ​2), poor performance status (n ​= ​5), decision to treat next with immunotherapy (n ​= ​3), and unknown (n ​= ​1). For the majority of lung cancer patients, the MTB provided recommendations based on tumor genetic profiles. Identified barriers to treatment suggest that presentation to the MTB at earlier stages of disease may increase the number of patients eligible for treatment with a genetically informed targeted agent., Competing Interests: The authors have no conflicts of interest to disclose., (© 2020 Published by Elsevier B.V.)

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10 -15 ) and replication (adjusted OR = 2.93, P = 2.22 × 10 -3 ) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10 -22 ) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

Introduction: Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor ( EGFR ) gene in non-small cell lung cancer (NSCLC) patients predicts response to EGFR tyrosine kinase inhibitors (TKIs). The Idylla™ system (Biocartis, Mechelen, Belgium) is a fully integrated, cartridge-based platform that provides automated sample processing and real-time PCR-based mutation detection in a single-use cartridge. This study evaluated the Idylla™ EGFR Mutation Assay cartridges against next-generation sequencing (NGS) using formalin fixed, paraffin embedded (FFPE) lung cancer tissue samples., Methods: Thirty-four FFPE lung adenocarcinoma tissue samples were tested on the Idylla™ system. 21 had at least one mutation in EGFR and 13 had no EGFR mutation as determined by NGS analysis using the Ion AmpliSeq 50-gene Cancer Hotspot Panel v2 (Thermo Fisher Scientific). One 10 ​μm FFPE tissue section was used for each Idylla™ test and all cases met the Idylla™ minimum tumor content requirement (≥10%)., Results: Idylla™ results were in complete agreement with those obtained by NGS for EGFR mutations targeted by the Idylla™. NGS identified two additional EGFR mutations that are not targeted by the Idylla™ in two samples (E709V and V774M). No EGFR mutations were detected by the Idylla™ in samples determined by NGS as having wild-type EGFR ., Conclusion: The fully automated Idylla™ system offers rapid and reliable testing for clinically actionable mutations in EGFR directly from FFPE tissue sections. Its simplicity and ease of use compared to other available molecular techniques make it suitable for routine clinical use in a variety of settings., Competing Interests: M. Rabie Al-Turkmani – received travel funds from Biocartis to present study findings at a national meeting. MAS, SJD, DCG, CCB, KS, KHD – no conflicts of interest to report. Gregory J. Tsongalis – Biocartis supported this study by providing cartridges., (© 2020 The Authors. Published by Elsevier B.V.)

Background: Small-cell lung cancer (SCLC) has a poor prognosis since there is currently no effective therapy for commonly recurring disease. In our previous study, both primary and recurrent human tumors have been shown to express functional N -methyl-D-aspartate (NMDA) receptors, and blockade of these receptors with GluN1 and GluN2B antagonists decreased tumor cell viability in vitro, and growth of tumor xenografts in nu/nu mice., Materials and Methods: In this study, we examine the influence of the GluN2B antagonist ifenprodil and the channel-blocker antagonist memantine, on cell viability and growth of tumor xenografts of recurrent SCLC (rSCLC) in mice., Results: Both antagonists significantly reduced cell viability and levels of components of the ERK1/2 pathway, increased apoptosis, and at very safe levels significantly reduced the growth of tumors in mice. Each antagonist and topotecan had additive effects to reduce cell viability with significant synergy demonstrated for the case of memantine. More significantly, combination treatments of xenografts in mice with ifenprodil and the chemotherapeutic agent topotecan produced clear additive effects that completely stopped tumor growth. Moreover, the ifenprodil and topotecan combination showed excellent supra-addition or synergy of inhibition for tumors ≤300 mm in size ( P =4.7E-4). Combination treatment of memantine with topotecan also showed clear addition but, unlike ifenprodil, no synergy for the doses chosen., Conclusion: Since topotecan is a drug of choice for treatment of rSCLC, our findings suggest that combining this agent with NMDA receptor blockade using the GluN2B antagonist, ifenprodil, will significantly improve patient outcomes., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: Randomized controlled trials (RCTs) of early palliative care interventions in advanced cancer have positively impacted patient survival, yet the mechanisms remain unknown. This secondary analysis of 2 RCTs assessed whether an early palliative care intervention moderates the relationship between depressive symptoms and survival., Method: The relationships among mood, survival, and early palliative care intervention were studied among 529 advanced cancer patients who participated in 2 RCTs. The first (N = 322) compared intervention versus usual care. The second (N = 207) compared early versus delayed intervention (12 weeks after enrollment). The interventions included an in-person consultation, weekly nurse coach-facilitated phone sessions, and monthly follow-up. Mood was measured using the Center for Epidemiologic Studies-Depression (CES-D) scale. Cox proportional hazard analyses were used to examine the effects of baseline CES-D scores, the intervention, and their interaction on mortality risk while controlling for demographic variables, cancer site, and illness severity., Results: The combined sample was 56% male (M = 64.7 years). Higher baseline CES-D scores were significantly associated with greater mortality risk (hazard ratio [HR] = 1.042, 95% confidence interval [CI] [1.017, 1.067], p = .001). However, participants with higher CES-D scores who received the intervention had a lower mortality risk (HR = .963, CI [0.933, 0.993], p = .018) even when controlling for demographics, cancer site, and illness-related variables., Conclusion: This study is the first to demonstrate that patients with advanced cancer who also have depressive symptoms benefit the most from early palliative care. Future research should be devoted to exploring the mechanisms responsible for these relationships. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Activation of the epidermal growth factor receptor (EGFR) pathway has been implicated in tumorigenesis in non-small cell lung cancer (NSCLC), the most common type of lung cancer. As a result, EGFR has become a key focus for the development of personalized therapy, with several molecular biomarkers having been investigated as potential predictors of response with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC (e.g., EGFR expression, EGFR gene copy gain, and EGFR mutations). Of these, activating mutations in EGFR have thus far given the most consistent results based on the available evidence from preclinical studies and clinical trials. In an attempt to identify patients who are most likely to benefit from treatment with EGFR TKIs, EGFR mutation testing is being increasingly utilized in clinical practice. Currently in the United States, no EGFR TKI or accompanying mutational test is approved for the identification and first-line treatment of patients with advanced NSCLC. However, the first-generation EGFR TKIs, erlotinib and gefitinib, as well as investigational ErbB family TKIs and EGFR mutation testing methods are being evaluated in this setting. This review will discuss EGFR mutation testing as a biomarker of response to EGFR TKIs and the evolution of EGFR mutational analysis in NSCLC. Completed and ongoing clinical trials evaluating currently available or investigational EGFR TKIs as first-line therapy in molecularly and clinically selected patients with NSCLC, with a focus on trials in patients whose tumors have EGFR mutations, will also be reviewed., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This dose-escalation study was performed to determine the recommended phase II dose of oral capecitabine to be delivered concurrently with thoracic radiation therapy and weekly docetaxel in patients with locally advanced esophageal carcinoma., Methods: Patients with operable stage II or III esophageal carcinoma were staged by endoscopic ultrasonography and computed tomography. Two cycles of docetaxel (80 mg/m) and carboplatin (target area under the concentration-time curve: 6 mg/ml × min) were delivered over 6 weeks. This was followed by concurrent weekly docetaxel (15 mg/m), thoracic radiotherapy (50.4 Gy in 28 fractions), and increasing doses of capecitabine (500-3500 mg) given before each fraction of radiotherapy. After restaging, responding patients continued to esophagectomy within 4 to 8 weeks of completing chemoradiotherapy., Results: Forty-four patients were enrolled, and 40 were assessable for the dose-ranging component of concurrent chemoradiotherapy. Endoscopic ultrasonography stages at enrollment were T3N1 (29 patients), T3N0 (4 patients), T2N1 (6 patients), and T4N0 (one patient). The maximum tolerated dose of capecitabine was 3500 mg. Thirty-six patients had surgery; 83% had R0 resection, and 17% had pathological complete response. Median overall survival was 23.5 months, with 34 and 27% alive at 3 and 5 years., Conclusion: The recommended phase II dose of capecitabine is 3500 mg when given concurrently with 50.4 Gy of thoracic radiotherapy in 28 fractions and weekly docetaxel. This trimodality therapy for operable locally advanced esophageal carcinoma was very well tolerated and remarkably active. This regimen holds promise for the treatment of esophageal carcinoma and warrants further investigation.

Tobacco carcinogen treatment of immortalized human bronchial epithelial (HBE) cells has uncovered novel targets for cancer chemoprevention. Experiments were conducted with HBE cells and independent treatments with tobacco carcinogens along with the chemopreventive agent all-trans-retinoic acid (RA). That work highlighted D-type and E-type cyclins as novel molecular pharmacologic targets of several chemopreventive agents. G1 cyclins are often aberrantly expressed in bronchial preneoplasia and lung cancers. This implicated these species as targets for clinical cancer chemoprevention. Retinoid regulation mechanisms of D-type cyclins in lung cancer chemoprevention have been comprehensively explored. Retinoid chemoprevention has been mechanistically linked to proteasomal degradation of cyclin D1 and cyclin D3. Threonine 286 mutation stabilized cyclin D1, implicating phosphorylation in this retinoid chemoprevention. Studies with a phospho-specific anti-cyclin D1 antibody confirmed this hypothesis. Glycogen synthase kinase (GSK) inhibitors established a role for this kinase in the retinoid regulation of cyclin D1, but not cyclin D3. Involvement of D-type cyclins in this chemoprevention was shown using small interfering RNAs (siRNAs). Gene profiling experiments highlighted the E1-like ubiquitin-activating enzyme (UBE1L) in the retinoid regulation of cyclin D1. Proof of principle trials have translated these studies into the clinic and established that chemopreventive agents can target D-type cyclins. These findings have been built upon with a targeted combination regimen that cooperatively affects D-type cyclins. Taken together, these preclinical and clinical findings strongly implicate these cyclins as novel molecular pharmacological targets for cancer chemoprevention.

The retinoids are natural and synthetic derivatives of vitamin A. These cancer therapeutic and chemopreventive agents exert anti-proliferative, differentiation-inducing, pro-apoptotic and other biological effects. The retinoids act through nuclear retinoid receptors to activate target genes that signal retinoid biological effects. Direct retinoid targets contain retinoid responsive elements in their promoters, are directly regulated by retinoids and reproduce retinoid biological effects once introduced into a responsive cell context. Through studies conducted in in vitro models, a proteolytic mechanism was linked to retinoid induced tumor cell differentiation and chemopreventive effects. Retinoid treatments can activate the proteasome-dependent degradation pathway. In acute promyelocytic leukemia (APL), all-trans-retinoic acid (RA) can also trigger degradation of the oncogenic protein, PML-RARalpha. Microarray analysis revealed involvement of an E1-like ubiquitin-activating enzyme, UBE1L, in this induction. Retinoid chemopreventive activity in human bronchial epithelial cells was linked to triggering of G(1) cell cycle arrest, concomitant growth suppression, and a decline in expression of G(1) cyclins. This can engage proteasome-dependent cyclin degradation, causing G(1) arrest and this permits repair of genomic DNA damage. The epidermal growth factor receptor (EGFR) was also identified as a retinoid target. Retinoids exert diverse biological effects. Different retinoid target genes likely trigger distinct effects. Identification of target genes is the next step towards a molecular understanding of mechanisms of retinoid response or resistance in cancer therapy and chemoprevention.

Purpose: There is a need to identify lung cancer prevention mechanisms. All-trans-retinoic acid (RA) was reported previously to inhibit N-nitrosamine-4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK) carcinogenic transformation of BEAS-2B human bronchial epithelial cells (J. Langenfeld et al., Oncogene, 13: 1983-1990, 1996). This study was undertaken to identify pathways targeted during this chemoprevention., Experimental Design: Because epidermal growth factor receptor (EGFR) overexpression is frequent in non-small cell lung cancers (NSCLC) and bronchial preneoplasia, BEAS-2B cells, carcinogen-transformed BEAS-2B(NNK) cells, and retinoid chemoprevented BEAS-2B(NNK RA) cells were each examined for EGFR expression. Whether RA treatment regulated directly EGFR expression or reporter plasmid activity was studied. RA effects on epidermal growth factor (EGF) induction of EGFR-phosphotyrosine levels, cyclin D1 expression and mitogenesis were examined in BEAS-2B cells., Results: Findings reveal that NNK-mediated transformation of BEAS-2B cells increased EGFR expression. RA treatment repressed EGFR expression and reporter plasmid activity in these cells. This treatment reduced EGF-dependent mitogenesis as well as EGFR-associated phosphotyrosine levels and cyclin D1 expression. These findings extend prior work by highlighting EGFR as a chemoprevention target in the lung. Notably, RA treatment prevented transformation as well as outgrowth of EGFR overexpressing bronchial epithelial cells, despite NNK exposure. After acute NNK exposure, p53-induced species that appear after DNA damage or oxidative stress were evident before an observed increase in EGFR expression., Conclusions: These findings indicate how effective chemoprevention prevents carcinogenic transformation of bronchial epithelial cells when repair of genomic damage does not select against EGFR overexpressing cells. This implicates EGFR as a chemoprevention target in the carcinogen-exposed bronchial epithelium.